Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid

Abstract

The invention is directed towards stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid and its hemisulfate salt as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.

The invention claimed is: 
     
       1. A method for treating breast cancer, esophageal cancer, gastric cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, colorectal cancer, osteosarcoma, liver cancer, pancreatic cancer, ovarian cancer, head and neck cancer, mesothelioma cancer, stomach cancer, bowel cancer, or lung cancer, comprising administering an effective amount of a pharmaceutical composition to a patient in need thereof, which composition comprises:
 A) a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, 
 B) a lyophilisate comprising the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid of A) or made therefrom, 
 C) a reconstituted solution from the lyophilisate of B), which has been reconstituted by water or a liquid pharmaceutically acceptable vehicle, 
 D) a lyophilisate comprising the sulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid or made therefrom without the presence of citrate, 
 E) a lyophilisate comprising 5,10-methylene-(6R)-tetrahydrofolic acid without the presence of citrate, or 
 F) a reconstituted solution from the lyophilisate of D) or E), which has been reconstituted by water or a liquid pharmaceutically acceptable vehicle. 
 
     
     
       2. A method for methotrexate therapy, comprising administering methotrexate to a subject in need thereof, and additionally administering
 A) a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, 
 B) a lyophilisate comprising the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid of A) or made therefrom, 
 C) a reconstituted solution from the lyophilisate of B), which has been reconstituted by water or a liquid pharmaceutically acceptable vehicle, 
 D) a lyophilisate comprising the sulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid or made therefrom without the presence of citrate, 
 E) a lyophilisate comprising 5,10-methylene-(6R)-tetrahydrofolic acid without the presence of citrate, or 
 F) a reconstituted solution from the lyophilisate of D) or E), which has been reconstituted by water or a liquid pharmaceutically acceptable vehicle. 
 
     
     
       3. A method for treating breast cancer, esophageal cancer, gastric cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, colorectal cancer, osteosarcoma, liver cancer, pancreatic cancer, ovarian cancer, head and neck cancer, mesothelioma cancer, stomach cancer, bowel cancer, or lung cancer, comprising administering an effective amount of a pharmaceutical composition to a patient in need thereof, which composition comprises a lyophilized formulation A, B, C, D or E,
 or a method for methotrexate therapy, comprising administering methotrexate to a subject in need thereof, and additionally administering a pharmaceutical composition comprising a lyophilized formulation A, B, C, D or E, 
 which 
 A) is prepared from a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, 
 B) comprises 5,10-methylene-(6R)-tetrahydrofolic acid and/or 5,10-methylene-(6R)-tetrahydrofolate resulting from a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, 
 C) comprises about two moles of 5,10-methylene-(6R)-tetrahydrofolic acid and/or 5,10-methylene-(6R)-tetrahydrofolate to one mole of sulfate ions, 
 D) comprises about 1 mole of 5,10-methylene-(6R)-tetrahydrofolic acid and/or 5,10-methylene-(6R)-tetrahydrofolate to one mole of sulfate ions without the presence of citrate, or 
 E) comprises 5,10-methylene-(6R)-tetrahydrofolic acid and/or 5,10-methylene-(6R)-tetrahydrofolate having a chemical purity of greater than 99%, and sulfate with the presence of citrate or without the presence of citrate; or 
 which is a stable pharmaceutical composition X or Y comprising 
 X) a lyophilised hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, which has such stability that the composition maintains greater than or equal to 95% of purity of the 5,10-methylene-(6R)-tetrahydrofolic acid for at least 24 months at +25° C./60% relative humidity; or for at least 12 months at +40° C./75% relative humidity, or for at least 24 months at +5° C., or for at least 24 months at −20° C.; or 
 Y) a reconstituted lyophilised hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, which has such stability that the composition maintains greater than or equal to 95% of purity of the 5,10-methylene-(6R)-tetrahydrofolic acid for at least 200 minutes at 2-8° C., or for at least 2 hours at room temperature. 
 
     
     
       4. A method according to  claim 1 , wherein the hemisulfate salt has been dissolved in water or in a liquid pharmaceutically acceptable vehicle, wherein the resultant solution has a pH of between 5 and 10.5. 
     
     
       5. A method according to  claim 1 , wherein the hemisulfate salt is in crystalline form, wherein the hemisulfate salt has one or more X-ray pattern peak positions at an angle of diffraction 2 theta of 4.7°, 17.9°, and 23.3° expressed in 2θ±0.2° 2θ CuKα radiation, reflection; or wherein the hemisulfate salt has a FT-Raman spectrum containing one or more peaks at wavenumbers, expressed in ±2 cm −1 , of 1672, 1656, 1603, 1553, 1474, 1301, 637, 624 and 363; or wherein the hemisulfate salt has a FT-Raman spectrum substantially in accordance with  FIG. 1 ; or wherein the hemisulfate salt has an X-ray powder diffraction pattern substantially in accordance with  FIG. 2( a ) ; or wherein the hemisulfate salt has an X-ray powder diffraction pattern substantially in accordance with  FIG. 2( b ) . 
     
     
       6. A method according to  claim 1 , wherein the hemisulfate salt has a stereoisomeric purity of greater than 99%; or has a chemical purity of greater than 99%. 
     
     
       7. A method according to  claim 1 , wherein in the lyophilisate the molar ratio between the (6R)-5,10-CH 2 -THF and sulfuric acid moieties is from about 1:1 to about 2:1. 
     
     
       8. A method according to  claim 1 , wherein the hemisulfate salt is in a pharmaceutical composition that also comprises a buffer, which buffer is citrate, phosphate, acetate, TRIS, N-tris(hydroxymethyl) methyl-2-aminoethanesulfonic acid (TES), 3-(N-morpholino) propanesulfonic acid (MOPS), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), MES, MOPSO, HEPES, succinate, carbonate, ammonium, mono-, di- or tri-alkylammonium, mono-, di- or tri-hydroxylalkylammonium, maleate, glutamate, borate, lactate or a combination thereof. 
     
     
       9. A method according to  claim 3 , wherein colorectal cancer is treated, which is metastatic colorectal cancer. 
     
     
       10. A method according to  claim 3 , wherein lung cancer is treated, which is adenocarcinoma. 
     
     
       11. A method according to  claim 1 , wherein colorectal cancer is treated, which is metastatic colorectal cancer. 
     
     
       12. A method according to  claim 1 , wherein lung cancer is treated, which is adenocarcinoma. 
     
     
       13. A method according to  claim 1 , wherein colon cancer, rectal cancer, colorectal cancer or bowel cancer is treated. 
     
     
       14. A method according to  claim 1 , wherein gastric cancer or stomach cancer is treated. 
     
     
       15. A method according to  claim 1 , wherein breast cancer or ovarian cancer is treated. 
     
     
       16. A method according to  claim 1 , wherein gall bladder cancer, bile duct cancer, liver cancer or pancreatic cancer is treated. 
     
     
       17. A method according to  claim 1 , wherein esophageal cancer is treated. 
     
     
       18. A method according to  claim 1 , wherein osteosarcoma is treated. 
     
     
       19. A method according to  claim 1 , wherein head and neck cancer is treated. 
     
     
       20. A method according to  claim 1 , wherein mesothelioma cancer is treated.